Friday, March 2, 2018

Organoids: an endgame for in vitro assay physiological relevance?

My career has been witness to a remarkable progression in the physiological relevance of in vitro assays used in preclinical drug discovery. The 90’s were characterized by industrialized high throughput screening of small chemical compounds for binding to purified proteins. Often millions of chemicals were screened and the protein’s relevance to disease was sketchy, sometimes linked only by their newly discovered DNA sequence.

10x z-projected image of mouse small intestinal organoid

Times have changed. With the turning of the millennium, these so-called biochemical binding assays were replaced by cell-based assays. At first, easy-to-culture cell lines such as CHO and HEK-293 were used with putative drug target protein overexpressed in them. These have given way to the use of cell types more consistent with the disease (i.e. β-islets for diabetes, neurons and astrocytes for Alzheimer’s). In addition, cells are being grown into structures that resemble tissues using various methods generally described as 3D cell culture.

Yet the most exciting development is the use of organoids, human stem cells that have been coaxed into clusters of differentiated cells that resemble our organs in miniature. As an example, a recent science article provides instructions on how to build a brainin vitro. I think the only way to provide more physiological relevance for an in vitro assay is to miniaturize a human being...

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